Halogen exchange reaction for preparing ring-fluorinated heteroaromatic compounds

Abstract

A one-step process is disclosed for preparing a compound of formula (I) (RZ)mArFn, by reacting a compound of formula (II) (RZ)mArYn with a source of fluoride in the presence of at least one compound of formula (III) wherein Ar denotes a substituted or unsubstituted monocyclic or polycyclic nitrogen-containing heteroaryl moiety and RZ, R1, R2, R3, R4, R5, X-, Y, m and n are as defined in the claims.

Description

[0001] 111518 FF

[0002] 1

[0003] HALOGEN EXCHANGE REACTION FOR PREPARING RING-FLUORINATED HETEROAROMATIC COMPOUNDS

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to an improved one-step process for preparing ring-fluorinated heteroaromatic compounds by a halogen exchange reaction of one or more halogen substituents of an heteroaromatic compound in the presence of a catalyst. It furthermore also relates to the catalyst composition, and its use in the process.

[0006] BACKGROUND OF THE INVENTION

[0007] Ring-fluorinated heteroaromatic compounds are important intermediates for preparing biologically active substances for pharmaceutical and agrochemical use.

[0008] The Halex (halogen exchange) process is a process known to convert aromatic chlorides to the corresponding aromatic fluorides. Classical reaction conditions typically used for highly activated nitrosubstituted aryl chlorides include reacting a solution of the aryl chloride and anhydrous potassium fluoride in aprotic, strongly polar solvents at elevated temperatures, such as in the range of from 150 to 250 °C. Typical solvents include dimethylsulfoxide, dimethylformamide, or sulfolane.

[0009] More recently, the reaction has been successfully carried out with less active aryl halide compounds, whereby 2-azaallenium, carbophosphazenium, aminophosphonium or diphosphazenium salts, alkylammonium salts, alkylphosphonium salts, tetraamidophosphonium salts, pyridinium salts, or crown ethers were employed as phase transfer catalysts. However, such reactions, especially for weakly activated aromatic halides, require high reaction temperatures and long reaction times, and due to the relatively low solubility not only have a high environmental impact due to the energy and solvent use footprint, but also deliver undesired by- and decomposition products in admixture with the desired products.

[0010] There is thus still a need for a reaction process that may suitably be carried out at lower temperatures, and requiring less or without the use of complex and instable phase transfer catalysts, to give access to weakly activated N-heteroaromatics for fluorine substituents in a halogen exchange reaction. This is particularly relevant for transforming N-heteroaromatic compounds into N-heteroaromatic fluorides. Accordingly, there is a need for a halogen exchange reaction process which does not have the above-detailed disadvantages of known processes and affords the corresponding ring-fluorinated, especially heteroaromatics compounds in good yields.

[0011] An object on which the present disclosure is based is therefore to provide a technically less cumbersome and generally more effective process as those known to date for preparing ring-fluorinated hetereoaromatic compounds by a halogen exchange reaction in good yield, with readily accessible phase transfer catalysts.

[0012] A further object is to provide for the use of a new catalyst class to be applied for this chemistry, in particular for a catalyst class with convenient synthetically access.111518 FF

[0013] 2

[0014] SUMMARY OF INVENTION

[0015] Applicants have now found that ring-fluorinated heteroaromatic compounds may be obtained in good yield, in the presence of specific catalysts. The present invention therefore provides a one-step process for preparing a compound (Rz)mArFn(I), by reacting a compound (Rz)mArYn(II) with a source of fluoride in the presence of at least one compound of general formula (III):

[0016]

[0017] wherein:

[0018] - Ar denotes a substituted or unsubstituted monocyclic or polycyclic nitrogen-containing heteroaryl moiety;

[0019] - Y represents a leaving group selected from chlorine, bromine, iodine, trifluoromethanesulfonyl (-tritiate), nitro (-NO2) or toluenesulfonyl (-tosyl);

[0020] - Rzdenotes one or more substituents selected from the group consisting of hydrogen (H), nitro (-NO2), halogen (Hal), cyano (-CN), -CORW, wherein Rwrepresents hydrogen, hydroxyl (-OH), phenoxy (-O-Ph), or an alkoxy substituent with an optionally substituted straight-chain or branched C1-C10 alkyl); a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 alkoxy, a substituted or unsubstituted C1-C4 haloalkyl wherein the halogen is selected from chlorine, bromine or iodine;

[0021] - m and n are natural numbers and together represent the number of ring atoms of Ar available to comprise a covalently bound substituent;

[0022] - wherein each individual R1, R2, R3, R4, and R5represents independently the same or different hydrogen, a straight-chain or branched C1-C12 alkyl, a C3-C8 cycloalkyl, a straight-chain or branched C2-C12 alkylene, a C3-C8 cycloalkylene, benzyl (-CH2-Ph), phenyl, imine, amidine, or guanidine; and - X-represents a suitable counter-anion.

[0023] In formulae I and II, Ar denotes a substituted or unsubstituted monocyclic or bicyclic aryl (-Ar-) moiety comprising at least one nitrogen ring atoms. In an embodiment, Ar may also denote a substituted or unsubstituted bisaryl (-Ar-Ar'-) moiety of a monocyclic aryl and / or bicyclic (-Ar-) aryl residue, wherein Ar and Ar' may be the same or different.

[0024] As used herein, the term ‘natural numbers’ refers to positive integers excluding the value 0. Hence, the sum of m + n is a positive integer, i.e. a natural number excluding the value 0. More preferably, the values for both m and n are positive integers. In formulas of the compound (Rz)mArYn(II) defined above it will be expected that the nitrogen atom in the ring is not available for covalent bonding. For example, in (Rz)mArYn, if Ar represents a pyridine ring, then m + n equals 5.

[0025] For example, Ar denotes a monocyclic aryl moiety comprising one or two nitrogen ring atoms, i.e. a pyridine, pyrimidine, pyrazine or pyridazine moiety. Alternatively, Ar may also denote a bicyclic aryl111518 FF

[0026] 3

[0027] moiety containing one or two nitrogen atoms. For instance, Ar denotes a quinoline, isoquinoline, benzodiazine or naphthyridine moiety.

[0028] Particularly advantageously, Ar may denote a substituted or unsubstituted pyridinyl, quinoline, or isoquinoline moiety. Most preferably, Ar denotes a pyridinyl moiety.

[0029] More particularly, in the process according to the present disclosure, Rzdenotes one or more substituents selected from the group consisting of hydrogen (H), nitro (-NO2), halogen (Hal), cyano (-CN), -CORWin particular aldehydes (i.e. where Rwis hydrogen), carboxyl (i.e. where Rwis -OH), and carboxylic acid esters (i.e. where Rwis phenoxy (-O-Ph), or an alkoxy substituent with an optionally substituted straight-chain or branched C1-C10 alkyl); a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 alkoxy, preferably a difluoroalkoxy or trifluoroalkoxy group, more preferably a difluoromethoxy or trifluoromethoxy group, a substituted or unsubstituted C1-C4 haloalkyl wherein the halogen is selected from chlorine, bromine or iodine, in particular a difluoromethyl (-CF2H) or trifluoromethyl (-CF3).

[0030] Preferably, X-represents a counter ion selected from tetrafluoroborate, triflate, bis(trifluoromethanesulfonyl)imide, trifluoroacetate (TFA), bisulfate, or chloride (Cl ).

[0031] In the process according to the present disclosure, Y represents a leaving group, such as chlorine, bromine or iodine, or an aryl or alkylsulfonate, such as trifluoromethanesulfonate, or any other similar leaving group that allows for the replacement by fluorine. Preferably, Y represents chlorine, bromine or iodine, trifluoromethanesulfonyl (-triflate), nitro (-NO2), or toluenesulfonyl (-tosyl), of which nitro (-NO2), chlorine, and bromine are preferred, in particular chlorine.

[0032] In the context of the invention, a one-step reaction means that isolation or workup of intermediates in the reaction are not required.

[0033] The alkyl groups occurring in the definitions of the substituents can be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, nonyl, decyl, dodecyl, and their branched isomers.

[0034] Alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkoxy, alkenyl and alkynyl radicals are derived from the alkyl radicals mentioned. The alkenyl and alkynyl groups can be mono- or polyunsaturated.

[0035] Halogen is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl or halophenyl. Haloalkyl groups preferably have a chain length of from 1 to 6 carbon atoms. Haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1 , 1 -difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl. In connection with the invention haloalkyl groups are preferably difluorochloromethyl, difluoromethyl, trifluoromethyl and dichlorofluoromethyl. Preferably, a haloalkyl group is difluoromethyl or trifluoromethyl.

[0036] Alkoxy groups preferably have a chain length of from 1 to 6 carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy and also the isomeric pentyloxy and hexyloxy radicals. In connection with the invention alkoxy groups are preferably methoxy and ethoxy.111518 FF

[0037] 4

[0038] Alkoxyalkyl groups preferably have a chain length of 1 to 6 carbon atoms. Alkoxyalkyl is, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl or isopropoxyethyl.

[0039] Alkoxycarbonyl is for example methoxycarbonyl (which is Ci alkoxycarbonyl), ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl or hexoxycarbonyl.

[0040] Alkylsulfanyl is for example methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, pentylsulfanyl, and hexylsulfanyl.

[0041] Alkylsulfinyl is for example methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, a butylsulfinyl, pentylsulfinyl, and hexylsulfinyl.

[0042] Alkylsulfonyl is for example methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0043] Cycloalkyl groups preferably have from 3 to 6 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0044] Haloalkoxy groups preferably have a chain length of from 1 to 4 carbon atoms. Haloalkoxy is, for example, difluoromethoxy, trifluoromethoxy or2,2,2-trifluoroethoxy.

[0045] Haloalkylsulfanyl groups preferably have a chain length of from 1 to 4 carbon atoms. Haloalkylsulfanyl is, for example, difluoromethylsulfanyl, trifluoromethylsulfanyl or 2,2,2-trifluoroethylsulfanyl. Similar considerations apply to the radicals C1-C4 haloalkylsulfinyl and C1-C4haloalkylsulfonyl, which may be, for example, trifluoromethylsulfinyl, trifluoromethylsulfonyl or 2,2,2-tri fluoroethylsulfonyl.

[0046] In the context of this invention "substituted" in the definition of the substituents, means typically, depending on the chemical structure of the substituents, monosubstituted to seven-times substituted, preferably monosubstituted to five-times substituted, more preferably mono-, double- or triplesubstituted. Free radicals represent methyl groups.

[0047] More particularly, the invention relates to a process for the manufacture of fluorohetereoaryl compounds according to general formula (la):

[0048]

[0049] by reacting a compound Rz-Ar-Y according to general formula (Ila):

[0050]

[0051] wherein Rzdenotes one or more substituents selected from the group consisting of hydrogen (H), nitro (-NO2), halogen (Hal), cyano (-CN), -CORW, in particular a carbaldehyde, carboxyl, or carboxylic acid ester as defined above in relation with compounds of formula (I) and (II); a substituted111518 FF

[0052] 5

[0053] or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 alkoxy, preferably a difluoroalkoxy or trifluoroalkoxy group, more preferably a difluoromethoxy or trifluoromethoxy group; a substituted or unsubstituted C1-C4 haloalkyl wherein the halogen is selected from chlorine, bromine or iodine, such as such as difluoromethyl (-CF2H) or trifluoromethyl (-CF3); and

[0054] wherein Y represents Cl, Br, I, trifluoromethanesulfonyl (-triflate), nitro (-NO2), or toluenesulfonyl (-tosyl), preferably wherein Y represents nitro, chlorine or bromine; yet more preferably Y represents chlorine.

[0055] More preferably, the process comprises reacting the compounds of formula (Ila) described above with a source of fluoride in the presence of at least one compound of the general formula (III):

[0056]

[0057] wherein each individual R1, R2and R3represents the same or different group selected from hydrogen, a straight-chain or branched C1-C12 alkyl, a C3-C8 cycloalkyl, a straight-chain or branched C2-C12 alkylene, a C3-C8 cycloalkylene, benzyl (-CFh-Ph), phenyl, imine, amidine, or guanidine, and R4and R5each independently represents hydrogen, a straight-chain or branched C1-C4 alkyl, a straightchain or branched C2-C4 alkylene, more preferably wherein one or both of R4and R5are methyl; wherein X-represents a counter-anion, preferably a counter ion selected from tetrafluoro bo rate, triflate, bis(trifluoromethanesulfonyl)imide, trifluoroacetate (TFA), bisulfate (HSO4 ) or chloride (Cl ).

[0058] More particularly, the invention relates to a process for the manufacture of a substituted or unsubstituted pyridine compound of general formula (lb):

[0059]

[0060] wherein the starting material is a substituted or unsubstituted pyridine compound of general formula (lib),

[0061]

[0062] 111518 FF

[0063] 6

[0064] wherein in formula (lb) and in formula (lib), R6, R7, R8and R9independently denote a substituent selected from the group consisting of hydrogen (-H), nitro (-NO2), halogen (-Hal), cyano (-CN), a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 alkoxy, preferably difluoroalkoxy or trifluoroalkoxy group; or

[0065] wherein R6and R7, or R7and R8, in formulae (lb) and (lib) together with the carbon atom they are bound to in the heteroaryl ring, form a substituted or unsubstituted homocyclic or nitrogen and / or oxygen containing heterocyclic 5- to 7-membered ring system; and

[0066] wherein in formula (lb) Y denotes a halogen selected from chlorine (Cl), bromine (Br) or iodine (I); trifluoromethanesulfonyl (triflate), nitro (-NO2) or toluenesulfonyl (tosyl); preferably Y denotes nitro, chlorine or bromine; most preferably Y denotes chlorine.

[0067] More particularly, the invention relates to a process for the manufacture of fluorohetereoaryl compounds having the formula (I) wherein the compound of formula (II) is a compound of formula (lib’)

[0068]

[0069] wherein R6, R7, R8and R9each individually represents hydrogen (-H), C1-C4 alkyl, phenyl (-Ph), cyano (-CN), carbaldehyde (-CHO), carboxyl (-COOH), carboxyl acid ester (-COOR10), wherein R10represents phenyl (-Ph), or a C1-C4 alkyl moiety.

[0070] Examples of such compounds of formula (lib’) include:

[0071]

[0072] wherein R11in compound of formula (Ilf) represents hydrogen (-H), phenyl (-Ph) ora C1-C4 alkyl moiety and R12in compound of formula (llg) represents cyano (-CN), a C1-C4 alkyl, carboxyl (-COOH), or a carboxylic acid ester (-COOR10) wherein R10represents phenyl or a C1-C4 alkyl moiety. In an embodiment, R10and R11represent independently tert-butyl or iso-propyl.

[0073] In a further embodiment, the invention relates to a fluorination process according to any one of the preceding embodiments described herein, related to the manufacture of the fluorinated products according to the invention, wherein the process comprises purifying and / or isolating the fluorinated product obtained to yield purified and / or isolated fluorinated products according to the invention.111518 FF

[0074] 7

[0075] In yet a further aspect, the invention relates to a fluorination process according to any one of the preceding aspects described herein, related to the manufacture of the fluorinated products according to the invention, wherein the purifying and / or isolating of the fluorinated product comprises or consists of a phase separation method.

[0076] In still a further embodiment, the invention relates to a fluorination process according to any one of the preceding embodiments described herein, related to the manufacture of the fluorinated products according to the invention, wherein the purifying and / or isolating does not comprise a distillation to yield purified and / or isolated fluorinated products according to the invention.

[0077] In a further aspect, the invention relates to a fluorination process according to any one of the preceding aspects described herein, wherein the catalyst according to formula (III) is selected as:

[0078]

[0079] wherein R1and R2each represents an alkyl, preferably a linear, branched or cyclic C1-C12 alkyl, more preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl dodecyl; cyclohexyl, each of which may be branched or substituted; such as benzyl;

[0080] wherein R3represents an alkyl, preferably a linear or branched C1-C10 alkyl, more preferably, a C1-C6 alkyl, more preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, or n-pentyl; and

[0081] wherein R4represents an hydrogen or alkyl, preferably a linear or branched C1-C10 alkyl, more preferably, a C1-C6 alkyl, more preferably methyl, ethyl, propyl, n-butyl, or n-pentyl; and

[0082] wherein X represents Cl, F, HSO4, BF4, PFe, triflate, bis(trifluoromethanesulfonyl)imide, and / or trifluoroacetate (TFA).

[0083] In a further aspect, the invention relates to the use of a compound having the general formula (III) as a phase transfer catalyst in a halogen exchange reaction:

[0084]

[0085] wherein each individual R1, R2, R3, R4and R5independently represents the same or different substituent selected from hydrogen, a straight-chain or branched C1-C12 alkyl, a straight-chain or branched C2-C12 alkylene, benzyl (-CFh-Ph), phenyl, imine, amidine, or guanidine; preferably, wherein R4and R5represent each independently hydrogen or a straight-chain or branched C1-C4 alkyl;

[0086] and wherein X-represents a counter anion;111518 FF

[0087] 8

[0088] preferably, wherein compound III is selected from 3-ethyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (Illa), 3-butyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (lllb), 3-dodecyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (lllc), 3-octyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (Hid), 1 -butyl-2, 3,4,5-tetramethyl-imidazol-1-ium chloride (llle), 1-(3,3-dimethylbutyl)-2,3-dimethyl-imidazol-1-ium chloride (lllf), 3-benzyl-1-dodecyl-2-methyl-1H-imidazol-3-ium chloride (Illg) and 3-butyl-1 ,2-dimethyl-1H-imidazol-3-ium bisulfate (lllh).

[0089] In a further aspect, the use of a compound of general formula (III) as a phase transfer catalyst in a halogen exchange reaction is in the presence of an alkali bisulfate salt, preferably sodium bisulfate or potassium bisulfate. Preferably, the alkali bisulfate salt is present in a range of from 1 to 40 mol% based on the amount of the compound of the general formula (I).

[0090] In a further aspect, the use of a compound of general formula (III) as a phase transfer catalyst in a halogen exchange reaction is in the presence of substituted nitrobenzene or non-substituted nitrobenzene, preferably nitrobenzene or 4-nitro-o-xylene. Preferably, the substituted nitrobenzene or non-substituted nitrobenzene is present in a range of from 1 to 40 mol% based on the amount of the compound of the general formula (I).

[0091] In yet a further aspect, the use of a compound of general formula (III) as a phase transfer catalyst in a halogen exchange reaction is in the presence both of an alkali bisulfate salt (preferably sodium bisulfate or potassium bisulfate) and of substituted nitrobenzene or non-substituted nitrobenzene (preferably nitrobenzene or 4-nitro-o-xylene). Preferably, the alkali bisulfate salt is present in a range of from 1 to 40 mol% based on the amount of the compound of the general formula (l)and the substituted nitrobenzene or non-substituted nitrobenzene is present in a range of from 1 to 40 mol% based on the amount of the compound of the general formula (I).

[0092] In an embodiment, in compound of formula (III), each of R1, R2, R3, R4, and R5independently represents hydrogen, a straight-chain or branched C1-C12 alkyl, a C3-C8 cycloalkyl, a straight-chain or branched C2-C12 alkylene, a C3-C8 cycloalkylene, benzyl (-CFh-Ph), imine, amidine, or guanidine. For instance, each of R1, R2, R3, R4, and R5independently represents hydrogen, a straight-chain or branched C1-C12 alkyl, a Cs-Cs cycloalkyl, a straight-chain or branched C2-C12 alkylene, a Cs-Cs cycloalkylene, or benzyl (-CFh-Ph). Also for instance, each of R1, R2, R3, R4, and R5independently represents hydrogen, a straight-chain or branched C1-C12 alkyl, or benzyl (-CFh-Ph).

[0093] Preferably, R1and R2each represents an alkyl, preferably a linear or branched C1-C12 alkyl, or a C3-C8 cycloalkyl; more preferably R1and R2each represents methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl; cyclohexyl, each of which may be branched or substituted; such as benzyl. Preferably, R1represents an alkyl, preferably a linear or branched C1-C12 alkyl, or a Cs-Cs cycloalkyl; more preferably R1represents methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl; cyclohexyl, each of which may be branched or substituted; such as benzyl.

[0094] Preferably, R2represents an alkyl, preferably a linear or branched C1-C12 alkyl, or a Cs-Cs cycloalkyl; more preferably R2represents methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl; cyclohexyl, each of which may be branched or substituted; such as benzyl.111518 FF

[0095] 9

[0096] Preferably, R3represents hydrogen, an alkyl, preferably a linear or branched C1-C10 alkyl, more preferably, R3represents a C1-C6 alkyl, more preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, or n-pentyl.

[0097] Preferably, each of R4and R5independently represents hydrogen or alkyl, preferably each of R4and R5independently represents a linear or branched C1-C10 alkyl, more preferably, a C1-C6 alkyl, more preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, or n-pentyl.

[0098] Preferably X represents Cl, F, HSO4, BF4, PFe, triflate, bis(trifluoromethanesulfonyl)imide, and / or trifluoroacetate (TFA).

[0099] Useful counter ion salts, preferably at a range of from 2 to 100 mol%, include NaHSC , KHSO4, NaBF4, KBF4, NaPFe, KPFe, sodium triflate, kalium triflate, sodium TFA, kalium TFA. Preferably, X represents Cl, F, HSO4, BF4, PFe, triflate, bis(trifluoromethanesulfonyl)imide, and / or trifluoroacetate (TFA).

[0100] Phase transfer catalysts (PTC) that were found particularly useful for the preparation of compounds according to Formula I were those where R2and R3each represents a methyl, and R1represents an ethyl, n-propyl or n-butyl residue. Also preferably, the counter anion found to be most effective was chloride. More specifically, particularly interesting phase transfer catalysts include compounds Illa, lllb, lllc, Hid, Hie, lllf and Illg:

[0101]

[0102] 111518 FF

[0103] 10

[0104]

[0105] A further particularly effective catalyst was found to be 3-butyl-1 ,2-dimethyl-1 H-imidazol-3-ium bisulfate (compound lllh), i.e. where counter anion X-is bisulfate:

[0106]

[0107] formula (III) as a phase transfer catalyst in a halogen exchange reaction

[0108]

[0109] wherein R1represents ethyl, butyl, octyl, dodecyl, 3,3-dimethylbutyl, or benzyl; R2represents methyl or dodecyl, preferably R2represents methyl; R3represent methyl; R4and R5independently represent hydrogen or methyl, preferably R4and R5represent hydrogen; and X-represents chloride (Cl ) or bisulfate (HSC ), preferably X-represents chloride (Cl ).

[0110] Hence, preferred phase transfer catalysts of general formula (III) include 3-ethyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (Illa), 3-butyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (lllb), 3-dodecyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (lllc), 3-octyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (Hid), 1-111518 FF

[0111] 11

[0112] butyl-2,3,4,5-tetramethyl-imidazol-1-ium chloride (Hie), 1-(3,3-dimethylbutyl)-2,3-dimethyl-imidazol-1-ium chloride (lllf), 3-benzyl-1-dodecyl-2-methyl-1H-imidazol-3-ium chloride (Illg) and 3-butyl-1 ,2-dimethyl-1H-imidazol-3-ium bisulfate (lllh).

[0113] The process according to the invention is preferably suitable for preparing compounds of the formula I, wherein R6, R7, R8, or R9in formula (Ila) denotes a cyano (-CN) residue. In the presence of water, cyano residues are prone to hydrolysis into the corresponding acid or amide depending on the pH of the reaction medium. Surprisingly, under the reaction conditions of the process according the invention, specifically a one-step process, very low levels of hydrolysis have been observed..

[0114] Accordingly, in a further aspect, the present invention also relates to a process according to the invention is preferably suitable for preparing compounds of the formula I alongside the hydrolysed free acid product, or directly the hydrolysed free acid.

[0115] The term “source of fluoride” includes fluorides, bifluorides, and tetrafluorides; such as for instance BF salts.

[0116] Useful sources of fluorides for the exchange of halogen for fluorine include, for example, fluorides, bifluorides, and tetrafluorides; such as for instance BF salts;, and alkali metal, alkaline earth metal and amino and ammonium fluorides.

[0117] Preference is given to potassium fluoride, sodium fluoride, calcium fluoride, caesium fluoride, ammonium fluoride as well as tetraalkyl fluorides N(RU)4F, where Ruis a C1-C4 alkyl, such as tetramethylammonium fluoride; tetraethylammonium fluoride, tetra-n-propyl ammonium fluoride ortetra-n-butylammonium fluoride, and also to their mixtures with one another and to their mixtures with lithium fluoride, rubidium fluoride and / or caesium fluoride. In an embodiment, the present process may advantageously be executed using NaF, KF, CsF, or tetra-n-butyl ammonium fluoride (TBAF) as the source of fluoride. It is noted that when the catalyst is mixed with a fluoride, a catalyst-fluoride complex of imidazolium fluorides may be formed in situ which may advantageously be employed as fluorination reagent.

[0118] The stoichiometry in the fluoride amount relative to the starting material may vary between at least 1 equivalent to 5 equivalents. Preferably the stoichiometry in the fluoride is in the range of from 1 to 2 equivalents to the starting material.

[0119] Based on 1 mol of halogen which is bonded to the ring of an aromatic compound and is to be exchanged for fluorine, for example, 0.001 to 0.5 mol, preferably 0.01 to 0.1 mol, of one or more compounds of the formula (III) and, for example, 0.8 to 2 equivalents, preferably 1.1 to 1.5 equivalents, of one or more halides may be used.

[0120] Preferably the stoichiometry in catalyst is in the range of from 1 to 100 mol%, more preferably of from 2 to 30 mol%, yet more preferably of from 3 to 25 mol%.

[0121] The compound(s) of the general formula (III) may be used in isolated form or in the form of solutions. Suitable solvents are, for example, dipolar aprotic and / or nonpolar aprotic solvents.

[0122] The process according to the invention is carried out preferably at temperatures in the range of 40 to 260 °C, more preferably at 70 to 240 °C. A particular preference is given to a temperature in the range of 140 to 220 °C, or more preferably, from 160 to 210 °C. Heating can be achieved with standard111518 FF

[0123] 12

[0124] equipment, such as an autoclave, a microwave equipment, a standard reactor, such as a double-jacket reactor, or a standard two-neck flask.

[0125] The process according to the invention may be carried out in the presence or in the absence of solvents. Preference is given to carrying out the process according to the invention in the presence of at least one solvent. Suitable solvents include, for example, dipolar aprotic and / or nonpolar aprotic solvents. Suitable dipolar aprotic solvents are, for example, dimethyl sulphoxide, sulfolane, dimethylformamide, dimethylacetamide, 1 ,3-dimethylimidazolin-2-one, N-methylpyrrolidone, acetonitrile and benzonitrile. Suitable nonpolar aprotic solvents are, for example, benzene, toluene. The above-listed solvents are likewise suitable for the solutions of the compound(s) of the general formula (III). When employing sulfolane, it preferably is present in an amount of from 0.5 to 2 mL / mmol, based on the starting material.

[0126] Non-polar aprotic and dipolar aprotic solvents may be used in any amounts, for example in amounts of 0.1 to 500% by weight, preferably in amounts of 0.2 to 300% by weight, based in each case on the heteroaromatic compound of general formula (I). Mixtures of solvents may also be employed, whereby preference is given to using solvent mixtures which comprise 50% by weight or more dipolar aprotic solvents.

[0127] It is also possible to carry out the process according to the invention in the presence or in the absence of free-radical scavengers or quenchers. Such radical quenchers include for instance nitrobenzene or nitroxylene. Particularly suitable free-radical scavengers or quenchers include, for example, BHT or aromatic nitro compounds, preferably nitrobenzene, 3-nitrodimethylbenzamide or 1 ,3-dinitrobenzene, or nitroxylenes, more preferably nitrobenzene or 1 ,2-dimethyl-4-nitrobenzene. The free-radical scavengers may be used in an amount of from 1 to 100 mol % based on the amount of the compound of the general formula (I). The use of free-radical scavengers may allow to distinctly reduce the formation of by-products by dehalogenation. In particular the presence of such quenchers in an amount of 2 to 100 mol% may aid under certain conditions.

[0128] It is also possible to carry out the process according to the invention in the presence of an alkali bisulfate salt. Suitable alkali bisulfate salts include, for example, sodium bisulfate and potassium bisulfate, The alkali bisulfate salt may be used in an amount of from 2 to 100 mol% based on the amount of the compound of the general formula (I). Preferably, the alkali bisulfate salt may be used in an amount of from 2 to 30 mol%, yet more preferably of from 10 to 30 mol% based on the amount of the compound of the general formula (I). It has been found that the use of an alkali bisulfate salt may allow to distinctly reduce the formation of by-products by degradation of reactants and therefore an improvement of the mass balance of the process.

[0129] The reaction time in the process according to the invention may, for example, be in the range of from 2 to 48 hours.

[0130] The process according to the invention may be carried out at reduced, standard or elevated pressure. Preference is given to working at standard pressure or elevated pressure, for example at 1 bar to 16 bar, for instance at a pressure ranging from 2 bar to 10 bar, most preferably at a pressure of from 1 bar to 5 bar.111518 FF

[0131] 13

[0132] In principle, the compounds of the formula (I) may be handled in the presence or absence of atmospheric oxygen. However, preference is given to handling the compounds of the formula (I) under protective gas and to carrying out the process according to the invention under protective gas. Suitable protective gases are, for example, nitrogen and argon.

[0133] The process according to the invention can be carried out batchwise or continuously.

[0134] To work up the reaction mixture present after the process according to the invention has been carried out, the procedure may be, for example, to mix the reaction mixture, after cooling, with water, remove the organic phase which forms and fractionally distil the removed organic phase under reduced pressure. The reaction mixture present after the process according to the invention has been carried out may also be subjected directly to a distillation. In addition, it is possible to add a solvent to the reaction mixture, remove solid constituents by filtration and distil the filtrate under reduced pressure. Furthermore, the product of the general formula (I) may also be removed from the reaction mixture by means of distillation under reduced pressure (pressure distillation). Other workup means or conditions can also be employed.

[0135] The preparation of the catalysts of the general formula (III) may conveniently be performed as set out in the literature, as for instance for 1-ethyl-2,3-dimethylimidazolium chloride (CAS Number 92507-97-6), 3-Benzyl-1-dodecyl-2-methyl-1 H-imidazol-3-ium chloride (CAS Number 21054-72-8); 1 ,3-Didodecyl-2-methyl-1H-imidazol-3-ium chloride (CAS Number 21054-71-7), 1-Butyl-2,3-dimethyl-3-imidazolium chloride (CAS Number 98892-75-2), or 1 ,2-Dimethyl-3-octyl-1H-imidazol-3-ium chloride (CAS Number 1007398-58-4).

[0136] The process according to the invention may also be useful for preparing doubly or multiply ring-fluorinated heteroaromatic compounds, preferably where said heteroaromatic compound contains a nitrogen ring atom. As it requires a one step, it thus entails a lower level of process technology complexity with regard to materials, energy and reaction vessels. In addition, the target products can be obtained with at least comparable, usually higher yield compared to the processes disclosed in the prior art. The process according to the invention is therefore a distinctly improved process compared to the prior art.

[0137] The following illustrative examples serve to illustrate the invention and are not to be interpreted as a restriction of the disclosure of the invention.

[0138] EXAMPLES

[0139] Abbreviations

[0140] BHT 2,6-di-tert-butyl-4-methylphenol

[0141] CCP 5-chloro-3-cyanopyridine

[0142] COCI 5-chloropyridine-3-carboxylic acid

[0143] COF 5-fluoropyridine-3-carboxylic acid

[0144] CP 3-cyanopyridine

[0145] DABCO 1 ,4-diazabicyclo[2.2.2]octane

[0146] DMSO-de deuterated dimethyl sulfoxide

[0147] eq. equivalents111518 FF

[0148] 14

[0149] FCP 5-fluoropyridine-3-carbonitrile

[0150] h hour / hours

[0151] KF potassium fluoride

[0152] KHSO4 potassium bisulfate

[0153] MeSChH methanesulfonic acid

[0154] Ph phenyl (C6H5-)

[0155] PTC phase-transfer-catalyst

[0156] n.d. not detectable

[0157] NMR nuclear magnetic resonance

[0158] TMB 1 ,3,5-trimethoxybenzene

[0159] ZrCk zirconium(IV) chloride

[0160] PREPARATORY EXAMPLES

[0161] The compounds of Formula (I) according to the invention may be prepared using the synthetic techniques described both above and below.

[0162] Throughout this description, temperatures are given in degrees Celsius (°C).1H NMR measurements were recorded on a Bruker 500MHz spectrometer. Chemical shifts are given in ppm relevant to a TMS (1H) standard. Spectra were measured in deuterated solvents as indicated.

[0163] Method used to quantify the amount of product and byproducts by NMR

[0164] Before taking a sample, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds. Then, another vial was charged with internal standard TMB (approx. 35 mg) and sample (approx. 250 mg for reaction mass). The resulting mixture was then dissolved in DMSO-de or CDCh (approx. 2-3 mL), After shaking, the contents were directly filtered through a syringe filter (0.2 pm) into an NMR tube and a quantitative1H NMR experiment was recorded on a Bruker 400 MHz spectrometer.

[0165] Example 1: Preparation of 5-fluoropyridine-3-carbonitrile

[0166]

[0167] An inlet of an autoclave is charged with 5-chloro-3-cyanopyridine (98%, 8.49 g, 60 mmol), potassium fluoride (99%, 5.28 g, 90 mmol), 1-ethyl-2,3-dimethylimidazolium chloride (94.9%, 1.93 g, 12 mmol), potassium bisulfate (99%, 2.17 g, 16 mmol) and sulfolane (60 mL). The inlet is placed in a PPR reactor and after sealing the reactor, the atmosphere is changed to nitrogen through pressurizing the reactor with nitrogen (5 bar) followed by realizing the pressure. Then, the content of the reactor is pressurized with nitrogen (2 bar) and the reaction mass is warmed to Ti = 180-185 °C over 1 hour and stirred at this temperature for additional 3 hours. Afterwards the reaction mass is cooled to Ti = 20-25 °C and the overpressure is released. Then, the reaction mass is filtered through a pad of Celite Hyflo and the reactor is rinsed three times with sulfolane (15 mL) to yield 5-fluoropyridine-3-carbonitrile (137.4 g,111518 FF

[0168] 1.75 wt.%, 33% isolated yield) as a black solution in sulfolane. Furthermore, 32% chemical yield of 5-chloro-3-cyanopyridine was determined.

[0169] 1H NMR (500 MHz, DMSO-d6) 6 ppm: 8.93-8.91 (m, 2H), 8.40-8.43 (m, 1H).

[0170] 19F NMR (471 MHz, DMSO-d6) 6 ppm: -124.4 (d, J = 8.89, 1 .08 Hz).

[0171] Example 2: Preparation of 5-fluoropyridine-3-carbonitrile

[0172]

[0173] A three-neck flask (equipped with thermometer, septa and glass tube connected to a drying trap filled with CaCb) was charged with potassium fluoride (99%, 5.28 g, 90 mmol), potassium bisulfate (99%, 2.48 g, 18 mmol) and sulfolane (60 g). The resulting suspension was heated to Ti = 175-180 °C followed by addition of 5-chloro-3-cyanopyridine (98%, 8.49 g, 60 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 2.39 g, 12 mmol) and 3,4-dimethylnitrobenzene (98%, 0.46 g, 3 mmol). Afterwards the resulting reaction mass was stirred at Ti = 175-180 °C for 4 hours. During this time the glass tube was heated with a heat-gun from time to time to melt sublimated product and starting material to support flow back to reaction mixture. Then, the reaction mass was cooled to Ti = 35-40 °C and the reaction mass was filtered. After filtration, the three-neck flask was rinsed with sulfolane (3 x20 g) and this solution was used to wash the filter cake. Then, the filter cake was blow-dried for 15 minutes to yield 5-fluoropyridine-3-carbonitrile (130.3 g, 2.31 wt.%, 41% isolated yield) as a black solution in sulfolane. Furthermore, 43% chemical yield of 5-chloro-3-cyanopyridine was determined.

[0174] 1H NMR (500 MHz, DMSO-d6) 6 ppm: 8.93-8.91 (m, 2H), 8.40-8.43 (m, 1H).

[0175] 19F NMR (471 MHz, DMSO-d6) 6 ppm: -124.4 (d, J = 8.89, 1 .08 Hz).

[0176] Example 3: Preparation of fluorinated products derived from 3-bromo-5-chloropyridine

[0177]

[0178] A microwave vial (20 mL) equipped with a stirring bar is charged with 3-bromo-5-chloropyridine (98%, 2.95 g, 15 mmol), potassium fluoride (99%, 1.31 g, 22.5 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 600 mg, 3 mmol) and sulfolane (16 g) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 205 °C for 4 hours to give a black reaction mass (20.3 g) containing multiple fluorinated products in the amounts specified below.

[0179] Chemical yield to 3-fluoro-5-bromopyridine: 7% (0.85 wt.%)

[0180] 1H NMR (500 MHz, CDCb) 6 ppm: 8.41 (s, 1H), 8.32 (d, J = 2.44 Hz, 1H), 7.55 (dt, J = 7.93, 1.9 Hz, 1H).

[0181] 19F NMR (471 MHz, CDCb) 6 ppm: -123.5 (dd, J = 7.91 , 1.19 Hz).

[0182] Chemical yield to 3-fluoro-5-chloropyridine: 13% (1.23 wt.%)

[0183] 1H NMR (500 MHz, CDCb) 6 ppm: 8.35 (s, 1H), 8.33 (d, J = 2.44 Hz, 1H), 7.42 (dt, J = 8.24, 2.2 Hz, 1H).

[0184] 19F NMR (471 MHz, CDCb) 6 ppm: -124.3 (dd, J = 8.24, 1.08 Hz).

[0185] Chemical yield to 3,5-difluoropyridine: 13% (1.26 wt.%)111518 FF

[0186] 1H NMR (500 MHz, CDCb) 6 ppm: 8.36 (s, 2H), 7.16 (dd, J = 8.21 , 4.75 Hz, 1 H).

[0187] 19F NMR (471 MHz, CDCb) 6 ppm: -123.7 (d, J = 8.70 Hz).

[0188] Chemical yield unreacted 3-bromo-5-chloropyridine: 53% (7.50 wt.%)

[0189] Example 4: Preparation of 3-fluoro-5-methylpyridine

[0190]

[0191] A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-methylpyridine (98%, 1.95 g, 15 mmol), potassium fluoride (99%, 1.31 g, 22.5 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 600 mg, 3 mmol) and sulfolane (16 g) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 220 °C for 6 hours to give a black reaction mass (18.3 g) containing 3-chloro-5-methylpyridine (7.5 wt.%, 12.35 mmol, 82% chemical yield) and 3-fluoro-5-methylpyridine (0.75 wt.%, 1 .08 mmol, 7% chemical yield).

[0192] 19F NMR (471 MHz, CDCb) 6 ppm: -128.5 (dd, J = 10.1, 2.10 Hz).

[0193] Example 5: Preparation of fluorinated products derived from 3-bromo-5-chloropyridine-2-carbonitrile

[0194]

[0195] A microwave vial (20 mL) equipped with a stirring bar is charged with 3-bromo-5-chloropyridine-2-carbonitrile (98%, 3.33 g, 15 mmol), potassium fluoride (99%, 1.31 g, 22.5 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 600 mg, 3 mmol), potassium bisulfate (99%, 619 mg, 4.5 mmol) and sulfolane (15 g) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 160 °C for 4 hours to give a black reaction mass (21 g) containing multiple fluorinated products in the amounts specified below.

[0196] Chemical yield to 3-bromo-5-fluoropyridine-2-carbonitrile: 21% (2.97 wt.)

[0197] 1H NMR (500 MHz, DMSO-d6) 6 ppm: 8.81 (d, J = 2.15 Hz, 1H), 8.53 (dd, J = 8.13, 2.46 Hz, 1H).19F NMR (471 MHz, DMSO-d6) 6 ppm: -114.7 (d, J= 8.00 Hz).

[0198] Chemical yield to 3-fluoro-5-chloropyridine-2-carbonitrile: 27% (3.02 wt.%)

[0199] 1H NMR (500 MHz, DMSO-d6) 6 ppm: 8.72 (dd, J = 1.95, 0.91 Hz, 1H), 8.48 (dd, J = 9.04, 1.93 Hz, 1H).

[0200] 19F NMR (471 MHz, DMSO-d6) 6 ppm: -114.5 (dd, J = 8.88, 0.87 Hz).

[0201] Chemical yield to 3,5-difluoropyridine-2-carbonitrile: 18% (1.81 wt.%)

[0202] 1H NMR (500 MHz, DMSO-d6) 6 ppm: 8.67 (d, J = 2.07 Hz, 1 H), 8.32 (td, J = 8.21 , 2.32 Hz, 1 H).19F NMR (471 MHz, DMSO-d6) 6 ppm: -112.71 - -112.66 (m), -112.58 (dd, J = 11.3, 8.7 Hz).

[0203] Chemical yield unreacted 3-bromo-5-chloropyridine-2-carbonitrile: 23% (3.12 wt.%)111518 FF

[0204] 17

[0205] Example 6: Preparation of 5-fluoropyridine-3-carbonitrile

[0206]

[0207] A microwave vial (20 mL) equipped with a stirring bar is charged with 5-bromo-3-cyanopyridine (98%, 2.80 g, 15 mmol), potassium fluoride (99%, 1.32 g, 22.5 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 600 mg, 3 mmol), potassium bisulfate (99%, 619 mg, 4.5 mmol) and sulfolane (15 g) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours to give a black reaction mass (20.5 g) containing 5-fluoropyridine-3-carbonitrile (2.49 wt.%, 4.18 mmol, 28% chemical yield) and 5-bromo-3-cyanopyridine (6.92 wt.%, 7.75 mmol, 52% chemical yield).

[0208] 1H NMR (500 MHz, DMSO-d6) 6 ppm: 8.93-8.91 (m, 2H), 8.40-8.43 (m, 1H).

[0209] 19F NMR (471 MHz, DMSO-d6) 6 ppm: -124.4 (d, J = 8.89, 1 .08 Hz).

[0210] Example 7: Preparation of 3,5-difluoropyridine

[0211]

[0212] A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-fluoropyridine (98%, 2.01 g, 15 mmol), potassium fluoride (99%, 1.32 g, 22.5 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 600 mg, 3 mmol) and sulfolane (16 g) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 205 °C for 4 hours to give a black reaction mass (19.5 g) containing 3-chloro-5-fluoropyridine (7.66 wt.%, 9.54 mmol, 64% chemical yield) and 3,5-difluoropyridine (2.77 wt.%, 3.85 mmol, 26% chemical yield).

[0213] 1H NMR (500 MHz, CDCb) 6 ppm: 8.36 (s, 2H), 7.16 (dd, J = 8.21 , 4.75 Hz, 1 H).

[0214] 19F NMR (471 MHz, CDCb) 6 ppm: -123.7 (d, J = 8.70 Hz).

[0215] Example 8: Preparation of 3,5-difluoropyridine

[0216]

[0217] A microwave vial (20 mL) equipped with a stirring bar is charged with 3-bromo-5-fluoropyridine (98%, 2.69 g, 15 mmol), potassium fluoride (99%, 1.32 g, 22.5 mmol), 1-butyl-2,3-dimethylimidazolium chloride (94.9%, 600 mg, 3 mmol) and sulfolane (19 g) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 205 °C for 4 hours to give a black reaction mass (23.6 g) containing 3-bromo-5-fluoropyridine (8.20 wt.%, 9.63 mmol, 64% chemical yield) and 3,5-difluoropyridine (1.64 wt.%, 2.77 mmol, 18% chemical yield).

[0218] 1H NMR (500 MHz, CDCb) 6 ppm: 8.36 (s, 2H), 7.16 (dd, J = 8.21 , 4.75 Hz, 1 H).

[0219] 19F NMR (471 MHz, CDCb) 6 ppm: -123.7 (d, J = 8.70 Hz).111518 FF

[0220] 18

[0221] REACTION SCREENING

[0222] Various reaction screens were performed as follows:

[0223] Initial catalyst screen

[0224]

[0225] General procedure: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), catalyst (PTC-X, 0.4 mmol) and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 5 hours (results in brackets are chemical yields after 18 hours). After the end of the reaction, the pre-cooled reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken for quantitative NMR analysis.

[0226] Table A1 : Results of initial catalyst screen

[0227]

[0228] Without catalyst only trace amounts of products were detected in the reaction mass. PTC-1 comprises a bromide counter ion, and showed no conversion to the desired product (FCP) under the conditions applied. Changing the counter-ion to chloride (PTC-2) or bisulfate (PTC-3) resulted in chemical yields between 23-25% after 5 hrs. For PTC-3, more product was formed overnight, giving a chemical yield of 38% despite all other catalysts exhibiting product decomposition over longer reaction times. In all examples, the longer reaction time led to greater production of byproducts (CP, COF and111518 FF

[0229] 19

[0230] COCI). The performance of the new generation of catalysts was compared to a CNC catalyst as disclosed for instance in EP1616863A1 (PTC-4 in table A1).

[0231] Catalyst loading screen for PTC-2

[0232]

[0233] General procedure: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), 1-dodecyl-3-methylimidazolium chloride (99%, PTC-2, a mol%) and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 5 hours. After the end of the reaction, the pre-cooled reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken for quantitative NMR analysis.

[0234] Table B1 : Results of catalyst loading screen for PTC-2

[0235]

[0236] As shown by examples in Table B1 (entries B.1 to B.4), 10 mol% was found to be the optimum in terms of chemical yield and mass balance. Using 20 mol% PTC-2 only slightly improved the chemical yield of the desired product FCP, but more CP byproduct was formed during this reaction.

[0237] Catalyst loading screen for PTC-3

[0238]

[0239] 111518 FF

[0240] 20

[0241] General procedure: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), 1-dodecyl-3-methylimidazolium bisulfate (99%, PTC-3, a mol%) and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 5 hours (results in brackets are chemical yields after 18 hours). After the end of the reaction, the pre-cooled reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken for quantitative NMR analysis.

[0242] Table C1 : Results of catalyst loading screen for PTC-3

[0243]

[0244] With respect to the impact on PTC-3, which comprised a bisulfate counter-anion, a similar trend as for PTC-2 was observed, and 10 mol% was identified as a preferred catalyst loading concentration for this reaction. Again, longer reaction time resulted in slightly improved chemical yields for catalyst loadings of 2.5, 5 and 20 mol% but also formation of more undesired side products. On the other hand, when 10 mol% of PTC-2 was tested, a significant improvement in the chemical yield of FCP (+13%) was observed over night in combination with improved mass balance.

[0245] Additive screen for PTC-3

[0246]

[0247] General procedure: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), 1-dodecyl-3-methylimidazolium bisulfate (99%, PTC-3, 140.8 mg, 0.4 mmol), additive and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 5 hours. In table D1 below, results in brackets are chemical yields after 18 hours. After the end of the reaction, the pre-cooled reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken for quantitative NMR analysis.111518 FF

[0248] 21

[0249] Table D1 : Results of additive screen for PTC-3

[0250]

[0251] In terms of additives, only catalytic amount of the radical scavenger nitro-o-xylene (10 mol%) had a positive impact in lowering the amounts of the CP byproduct, even after longer reaction time. But, no significant yield improvement in FCP was seen. Large levels of decompositions were detected for catalytic amount of potassium carbonate or citric acid in combination with nitro-o-xylene.

[0252] Concentration screen for PTC-3

[0253]

[0254] General procedure: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), 1-dodecyl-3-methylimidazolium bisulfate (99%, PTC-3, 140.8 mg, 0.4 mmol), nitro-ortho-xylene (99%, 30.5 mg, 0.2 mmol) and sulfolane (a mL / mmol CCP) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 5 hours. After the end of the reaction, the pre-cooled reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken for quantitative NMR analysis.

[0255] Table E1 : Results of concentration screen for PTC-3

[0256]

[0257] 111518 FF

[0258] 22

[0259] No improvement was observed as a result of varying the concentration of the reaction. But, at lower reaction concentrations (Table E1 , entries E.3 and E.4) an around 10% lower chemical yield in FCP was reported in combination with a worser mass balance.

[0260] KF loading screen for PTC-3

[0261]

[0262] General procedure: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, a eq.), 1-dodecyl-3-methylimidazolium bisulfate (99%, PTC-3, 140.8 mg, 0.4 mmol), nitro-ortho-xylene (99%, 30.5 mg, 0.2 mmol) and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 5 hours. After the end of the reaction, the pre-cooled reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken for quantitative NMR analysis.

[0263] Table F1 : Results of KF loading screen for PTC-3

[0264]

[0265] No improvement was observed as a result of varying the loading of the potassium fluoride. Reaction set-up screen

[0266]

[0267] General procedure using standard heating: A screening vial (20 mL) equipped with a stirring bar and wrapped in aluminium foil is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), 1-dodecyl-3-methylimidazolium chloride (98%, PTC-2, 117.1 mg, 0.4 mmol) and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is stirred at 180 °C for 4 hours. After the end of the reaction, the reaction mass is warmed111518 FF

[0268] 23

[0269] to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0270] General procedure using microwave heating: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2827.5 mg, 20 mmol), potassium fluoride (99%, 1320.4 mg, 40 mmol), 1-dodecyl-3-methylimidazolium chloride (98%, PTC-2, 573.7 mg, 1.5 mmol) and sulfolane (20 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 180 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0271] Table G1 : Results of reaction set-up screen

[0272]

[0273] No large differences either in FCP chemical yield nor in mass balance were observed for the two tested reaction set-ups. But, to facilitate the screening efforts, all further screenings were performed in the microwave reactor using its automation capabilities. Furthermore, because sublimation tendency of educt (CCP) and product (FCP) reactions in closed vials under slight pressure might further improve the reactivity and / or mass balance.

[0274] Concentration screen for PTC-2

[0275]

[0276] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 1 eq.), potassium fluoride (99%, 2 eq.), 1-dodecyl-3-methylimidazolium chloride (98%, PTC-2, 10 mol%) and sulfolane (a mL / mmol CCP) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 180 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.111518 FF

[0277] 24

[0278] Table H1 : Results of concentration screen for PTC-2

[0279]

[0280] More concentrated reaction mixture (Table H1 , entry H.1 vs. H.2) resulted in a 8% lower mass balance, due to more decomposition. No significant effect was seen for more diluted reaction mass (Table H1 , entry H.2 vs H.3).

[0281] Temperature screen for PTC-2

[0282]

[0283] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1760.5 mg, 30 mmol), 1-dodecyl-3-methylimidazolium chloride (98%, PTC-2, 430.3 mg, 1.5 mmol), water (27 mg, 1.5 mmol) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at indicated temperature for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0284] Table 11 : Results of temperature screen for PTC-2

[0285]

[0286] Albeit slightly lower mass balance and formation of more CP, at higher reaction temperature an improved chemical yield of FCP was detected.

[0287] KF loading screen for PTC-2111518 FF

[0288] 25

[0289]

[0290] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, a eq.), 1-dodecyl-3-methylimidazolium chloride (98%, PTC-2, 430.3 mg, 1.5 mmol), water (27 mg, 1.5 mmol) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0291] Table J1 : Results of catalyst loading screen

[0292]

[0293] No improvement was observed as a result of varying the loading of the potassium fluoride. Reaction time screen for PTC-2

[0294]

[0295] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1100.3 mg, 18.8 mmol), 1-dodecyl-3-methylimidazolium chloride (98%, PTC-2, 430.3 mg, 1.5 mmol), water (27 mg, 1.5 mmol) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for the indicated time in Table K1. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.111518 FF

[0296] 26

[0297] Table K1 : Results of reaction time screen for PTC 2

[0298]

[0299] Longer reaction time (Table K1 , entry K.2 vs K.3) resulted in lower chemical yield of FCB in combination with formation of more CP byproduct and inferior mass balance due to decomposition. Additive screen for PTC-2

[0300]

[0301] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1320.4 mg, 22.5 mmol), catalyst (PTC-2, 430.3 mg, 1.5 mmol), additive (a mol%) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis. Table L1 : Results of additive screen for PTC-2

[0302]

[0303] No significant improvement was seen when catalytic amount of nitro-ortho-xylene was used as radical quencher. On the other hand, Example L.3 show the beneficial effect of potassium bisulfate in combination with catalytic amount of water in terms of stability of the reaction mixture and mass balance therefore. No beneficial effect was observed for DABCO as nucleophilic co-catalyst. Application of strong acids (Table L1 , entry L.5) and Lewis acids (Table L1 , entry L.6) resulted in inferior results.111518 FF

[0304] 27

[0305] Extended catalyst screen with catalytic amount of water and KHSO4

[0306]

[0307] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1320.4 mg, 22.5 mmol), catalyst (1.5 mmol), water (27 mg, 1.5 mmol), potassium bisulfate (98%, 208.4 mg, 1.5 mmol) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0308] Table M1 : Results of extended catalyst screen with additives

[0309] "

[0310] "

[0311]

[0312] Compared to prior-art catalyst CNC, no improved outcome of the reaction was observed for 1 ,3 substituted imidazolium chlorides, under best set of conditions. But, a significant improvement was achieved when 1 ,2-dimethyl-3-octylimidazolium chloride was tested. This results highlights the importance of the 1 ,2-dimethyl-imidazolium core unit in terms of reactivity and mildness (excellent mass balance).111518 FF

[0313] 28

[0314] Additive screen for 1-octyl-2,3-dimethyl-3-imidazolium chloride

[0315]

[0316] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1320.4 mg, 22.5 mmol), 1-octyl-2,3-dimethyl-3-imidazolium chloride (98%, 374.7 mg, 1.5 mmol), additive and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0317] Table N1 : Results of additive screen

[0318]

[0319] Addition of catalytic amount of potassium bisulfate had a positive impact on the chemical yield and over all mass balance. In combination with 4-nitro-o-xylene or nitrobeneze resulted in reduction of CP byproduct formation.111518 FF

[0320] 29

[0321] Revised catalyst screen 2

[0322]

[0323] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1320.4 mg, 22.5 mmol), catalyst (1.5 mmol), potassium bisulfate (98%, 312.6 mg, 2.25 mmol) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis. Table O1 : Results of revised catalyst screen

[0324]

[0325] For most tested catalyst similar results were obtained, with 1-ethyl-2,3-dimethylimidazolium chloride (Table O1 , entry 0.6) slightly outperforming compared to the other tested catalyst. On the other hand, for 3-benzyl-1-dodecyl-2-methyl-1H-imidazol-3-ium chloride (Table O1 , entry 0.4) a lower chemical yield to FCP was seen because of catalyst instability.111518 FF

[0326] 30

[0327] Optimization screen for 1-ethyl-2,3-dimethylimidazolium chloride

[0328]

[0329] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, c eq.), 1-ethyl-2,3-dimethyl-3-imidazolium chloride (98%, a mol%), potassium bisulfate (98%, b mol%) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0330] Table P1 : Results of optimization screen

[0331]

[0332] Improved chemical yield to FCP was observed for higher catalyst loadings. Lowering the amount of KF resulted in inferior results.

[0333] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 565.5 mg, 4 mmol), potassium fluoride (99%, 469.5 mg, 8 mmol), catalyst (0.4 mmol) and sulfolane (4 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 180 °C for 5 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0334] Counter-ion screen for catalysts

[0335]

[0336] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1320.4 mg, 22.5 mmol),111518 FF

[0337] 31

[0338] catalyst (3 mol%) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0339] Table Q1 : Results of counter ion of catalyst screen

[0340]

[0341] Only low reactivities were reported for other counter ions than chloride or bisulfate, highlighting the importance of chloride or bisulfate as counter ion in the catalyst structure.

[0342] Revised catalyst screen 3

[0343]

[0344] General procedure: A microwave vial (20 mL) equipped with a stirring bar is charged with 3-chloro-5-cyanopyridine (98%, 2120.6 mg, 15 mmol), potassium fluoride (99%, 1320.4 mg, 22.5 mmol), catalyst (3 mmol), potassium bisulfate (98%, 625.2 mg, 4.5 mmol) and sulfolane (15 mL) and the resulting suspension is vortexed for 30 seconds. Then, the vial is placed in a microwave reactor and stirred at 190 °C for 4 hours. After the end of the reaction, the reaction mass is warmed to 40 °C followed by vortexing of the reaction mass for 30 seconds, and a sample is taken to quantitative NMR analysis.

[0345] Table R1 : Results of revised catalyst screen

[0346]

[0347] 111518 FF

[0348] 32

[0349]

Claims

1. 111518 FF33CLAIMS1. A one-step process for preparing a compound of formula (I)(Rz)mArFn(I)by reacting a compound of formula (II)(Rz)mArYn(II)with a source of fluoride in the presence of at least one compound of formula (III):>wherein:Ar denotes a substituted or unsubstituted monocyclic or polycyclic nitrogen-containing heteroaryl moiety;Y represents a leaving group selected from chlorine, bromine, iodine, trifluoromethanesulfonyl (tritiate), nitro (-NO2), or toluenesulfonyl (tosyl);Rzdenotes one or more substituents independently selected from the group consisting of hydrogen (H), nitro (-NO2), halogen (Hal), cyano (-CN), -CORW(wherein Rwrepresents hydrogen, hydroxyl (-OH), phenoxy (-O-Ph), or an alkoxy substituent with an optionally substituted straight-chain or branched C1-C10 alkyl); a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted Ci-04 alkoxy, and a substituted or unsubstituted C1-C4 haloalkyl wherein the halogen is selected from chlorine, bromine or iodine;m and n are natural numbers and together represent the number of ring atoms of Ar available to comprise a covalently bound substituent;wherein each individual R1, R2, R3, R4and R5represents the same or different group selected from hydrogen, straight-chain or branched C1-C12 alkyl, C3-C8 cycloalkyl, straight-chain or branched C2-C12 alkylene, C3-C8 cycloalkylene, benzyl (-CH2-Ph), phenyl, imine, amidine, or guanidine; andX-represents a suitable counter-anion.

2. The process according to claim 1 , wherein in formulae (I) and (II), Ar denotes a substituted or unsubstituted heterocyclic monocyclic or bicyclic (-Ar-) aryl residue comprising at least one nitrogen ring atom;preferably, wherein Ar is a substituted or unsubstituted pyridinyl, quinoline, or isoquinoline moiety;more preferably wherein Ar is a substituted or unsubstituted pyridinyl moiety.

3. The process according to claim 1 or claim 2, wherein Ar is a substituted pyridinyl residue, wherein Rzdenotes one or more substituents selected from -CORW(wherein Rwrepresents hydrogen,111518 FF34hydroxyl, phenyl, or an alkoxy substituent with an optionally substituted straight-chain or branched Ci-C10 alkyl); difluoromethyl (-CF2H) or trifluoromethyl (-CF3); or cyano (-CN);preferably wherein (Rz)mArYnrepresents a 3-chloro-5-cyanopyridine.

4. The process according to any one of claims 1 to 3, wherein X-represents a counter ion selected from tetrafluoroborate, triflate, bis(trifluoromethanesulfonyl)imide, trifluoroacetate (TFA), bisulfate or chloride.

5. The process according to any one of claims 1 to 4, wherein Y represents chlorine (Cl), bromine (Br), iodine (I), trifluoromethanesulfonate (triflate) or toluenesulfonate (-O-SO2C6H4CH3, or tosylate); preferably, wherein Y represents chlorine or bromine: most preferably, wherein Y represents chlorine.

6. The process according to any one of claims 1 to 5, wherein compound of formula (I) is a compound of formula (la)obtained by reacting a compound of general formula (Ila) as compound of formula (II):wherein in compounds of formula (la) and of formula (Ila)Rzdenotes one or more substituents independently selected from the group consisting of hydrogen (H), nitro (-NO2), halogen (Hal), cyano (-CN), carbaldehyde (-CHO), carboxyl (-COOH), and carboxylic acid ester (-COR10), a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 alkoxy, preferably a difluoroalkoxy or trifluoroalkoxy group, more preferably a difluoro methoxy or trifluoromethoxy group, a substituted or unsubstituted C1-C4 haloalkyl wherein the halogen is selected from chlorine, bromine or iodine;R10represents phenyl (-Ph), or a C1-C4 alkyl moiety; andY represents nitro, chlorine (Cl), bromine (Br), iodine (I), trifluoromethane-sulfonate (triflate), or toluenesulfonate (-O-SO2C6H4CH3, tosylate); preferably, wherein Y represents chlorine or bromine; most preferably, wherein Y represents chlorine.

7. The process according to any one of claims 1 to 6, wherein compound of formula (I) is a compound of formula (lb)111518 FF35obtained by reacting a substituted or unsubstituted pyridinyl compound of general formula (lib) as compound of formula (II)wherein in compounds of formula (lb) and of formula (lib):R6, R7, R8, and R9independently denote a substituent selected from the group consisting of hydrogen (-H), nitro (-NO2), halogen (-Hal), cyano (-CN), carbaldehyde (-CHO), carboxyl (-COOH), and carboxyl acid ester (-COOR10), a substituted or unsubstituted C1-C4 alkyl, and a substituted or unsubstituted C1-C4 alkoxy, preferably difluoroalkoxy or trifluoroalkoxy group; where R10represents hydrogen (-H), phenyl (-Ph), or a C1-C4 alkyl moiety; orR6and R7, or R7and R8, together with the carbon atom to which they are bound to in the aryl ring, form a substituted or unsubstituted homocyclic or nitrogen and / or oxygen containing heterocyclic 5- to 7-membered ring system; andY denotes a substituent selected from chlorine (Cl), bromine (Br), iodine (I), trifluoromethanesulfonyl (triflate), nitro (-NO2), and toluenesulfonyl (tosyl); preferably Y denotes a substituent selected from nitro, chlorine, or bromine; most preferably Y is chlorine.

8. The process according to claim 7, wherein in the compound of formula (lib)R6, R7, R8and R9each individually represent hydrogen (-H), C1-C4 alkyl, phenyl (-Ph), cyano (-CN), carbaldehyde (-CHO), carboxyl (-COOH), carboxyl acid ester (-COOR10);wherein R10represents hydrogen (-H), phenyl (-Ph), or a C1-C4 alkyl moiety.111518 FF369. The process according to any one of claims 1 to 8, wherein the compound according to general formula (II) is selected from compounds (lie) to (llg):wherein R11in compound (Ilf) represents hydrogen (-H), phenyl (-Ph) or Ci-C4 alkyl moiety and R12in compound (llg) represents cyano (-CN), C1-C4 alkyl, a carboxyl (-COOH), or a carboxylic acid ester (-COOR10) wherein R10represents hydrogen, phenyl or a C1-C4 alkyl moiety;and preferably wherein compound of formula (II) is compound (lid): 3-chloro-5-cyanopyridine.

10. The process according to any one of claims 1 to 9, characterized in that the reaction is carried out in the presence of compounds of formula (III) wherein:each individual R1, R2and R3independently represents hydrogen, a straight-chain or branched C1-C12 alkyl, a straight-chain or branched C2-C12 alkylene, imine, amidine, or guanidine; and each individual R4and R5independently represents hydrogen, a straight-chain or branched C1-C4 alkyl, or a straight-chain or branched C2-C4 alkylene;preferably, wherein each individual R1and R2independently represents a straight-chain or branched C1-C12 alkyl, a straight-chain or branched C2-C12 alkylene; and wherein each individual R3, R4and R5independently represents hydrogen, a straight-chain or branched C1-C4 alkyl, ora straight-chain or branched C2-C4 -alkylene.

11. The process according to any one of claims 1 to 10, wherein a compound of the general formula (II) is contacted with at least one compound of the general formula (III) in a solvent for a time and under conditions suitable to replace one or more of Y with fluorine;wherein the reaction is carried out at a temperature of 40°C to 260°C; and / or wherein the process is carried out in the presence of dipolar aprotic and / or nonpolar aprotic solvents.

12. The process according to any one of claims 1 to 11 , wherein compound (III) is employed in the range of from 1 to 25 mol %; and / or wherein based on each mol of the leaving group Y which is bonded to the ring of the compound of formula (II) and is to be exchanged for fluorine, 0.001 to 0.5 mol of one or more compounds of the formula (III) and 0.8 to 2 equivalents of one or more sources of fluoride are employed.

13. The process according to any one of claims 1 to 12, wherein the source of fluoride comprises at least one alkali metal, alkaline earth metal or amino fluoride, bifluorides, and tetrafluorides.111518 FF3714. The process according to any one of claims 1 to 13, characterized in that the reaction is carried out in the presence of an alkali bisulfate salt, preferably in a range of from 1 to 40 mol% based on the amount of the compound of the general formula (I); preferably where the alkali bisulfate salt is sodium bisulfate, potassium bisulfate, or combinations thereof.

15. The process according to any one of claims 1 to 14, characterized in that the reaction is carried out in the presence of substituted nitrobenzene or non-substituted nitrobenzene, preferably in a range of from 1 to 40 mol% based on the amount of the compound of the general formula (I), preferably where the substituted or non substituted nitrobenzene is nitrobenzene or 4-nitro-o-xylene.

16. The use of a compound having the general formula (III):wherein each individual R1, R2, R3, R4and R5independently represents the same or different substituent selected from hydrogen, a straight-chain or branched C1-C12 alkyl, a C3-C8 cycloalkyl, a straight-chain or branched C2-C12 alkylene, a C3-C8 cycloalkylene, benzyl (-CFh-Ph), phenyl, imine, amidine, or guanidine; preferably, wherein R4and R5represent each independently hydrogen or a straight-chain or branched C1-C4 alkyl;and wherein X-represents a counter anion,as a phase transfer catalyst in a halogen exchange reaction.

17. The use according to claim 16, wherein X-is selected from tetrafluoroborate, triflate, bis(trifluoromethanesulfonyl)imide, trifluoroacetate (TFA), bisulfate or chloride (Cl ).

18. The use according to claim 16 or 17, in the presence of an alkali bisulfate salt, preferably sodium bisulfate or potassium bisulfate; or in the presence of substituted nitrobenzene or non-substituted nitrobenzene, preferably nitrobenzene or 4-nitro-o-xylene; or in the presence of an alkali bisulfate salt and of substituted nitrobenzene or non-substituted nitrobenzene.

19. The process according to any one of claims 1 to 15, or the use according to any one of claims 16 to 18, wherein compound of formula (III) is selected from 3-ethyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (Illa), 3-butyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (lllb), 3-dodecyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (lllc), 3-octyl-1 ,2-dimethyl-1H-imidazol-3-ium chloride (Hid), 1 -butyl-2, 3,4,5-tetramethyl-imidazol-1-ium chloride (llle), 1-(3,3-dimethylbutyl)-2,3-dimethyl-imidazol-1-ium chloride (lllf), 3-benzyl-1-dodecyl-2-methyl-1H-imidazol-3-ium chloride (Illg) and 3-butyl-1 ,2-dimethyl-1H-imidazol-3-ium bisulfate (lllh).

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